Cloral Hydrate

(BAN)
Cloral Hydrate Chemical formula

💊 Chemical information

Chloral Hydrate (BAN); Chloral, hydrate de; Chloralhydrát; Chlorali hydras; Chloralio hidratas; Chloralu wodzian; Cloral, hidrato de; Kloraalihydraatti; Kloral Hidrat; Klorál-hidrát; Kloralhydrat.
2,2,2-Trichloroethane-1,1-diol.
Chemical formula: C2H3Cl3O2 = 165.4.
CAS — 302-17-0.
ATC — N05CC01.
ATC Vet — QN05CC01.

Pharmacopoeias.

In Chin., Eur., Int., Jpn, US, and Viet.

Ph. Eur. 6.2

(Chloral Hydrate). Colourless, transparent crystals. Very soluble in water; freely soluble in alcohol. A 10% solution in water has a pH of 3.5 to 5.5. Store in airtight containers.

USP 31

(Chloral Hydrate). Colourless, transparent, or white crystals having an aromatic, penetrating, and slightly acrid odour. It volatilises slowly on exposure to air and melts at about 55°. Soluble 1 in 0.25 of water, 1 in 1.3 of alcohol, 1 in 2 of chloroform, and 1 in 1.5 of ether; very soluble in olive oil. Store in airtight containers.

Incompatibility.

Cloral hydrate is reported to be incompatible with alkalis, alkaline earths, alkali carbonates, soluble barbiturates, borax, tannin, iodides, oxidising agents, permanganates, and alcohol (cloral alcoholate may crystallise out). It forms a liquid mixture when triturated with many organic compounds, such as camphor, menthol, phenazone, phenol, thymol, and quinine salts.

💊 Dependence and Withdrawal, Adverse Effects, and Treatment

Cloral hydrate has an unpleasant taste and is corrosive to skin and mucous membranes unless well diluted. The most frequent adverse effect is gastric irritation; abdominal distension and flatulence may also occur. CNS effects such as drowsiness, lightheadedness, ataxia, headache, and paradoxical excitement, hallucinations, nightmares, delirium, and confusion (sometimes with paranoia) occur occasionally. Hypersensitivity reactions include skin rashes (erythema multiforme and Stevens-Johnson syndrome have been reported with the related compound triclofos). Ketonuria may occur. The effects of acute overdosage resemble acute barbiturate intoxication, and are managed similarly. In addition the irritant effect may cause initial vomiting, and gastric necrosis leading to strictures. Cardiac arrhythmias have been reported. Jaundice may follow liver damage, and albuminuria may follow kidney damage. Tolerance may develop and dependence may occur. Features of dependence and withdrawal are similar to those of barbiturates.

Incidence of adverse effects.

In a drug surveillance programme,1 adverse effects of cloral hydrate, which were reversible, occurred in 2.3% of 1130 patients evaluated and included gastrointestinal symptoms (10 patients), CNS depression (20), and skin rash (5). In 1 patient the prothrombin time was increased; in 1 patient hepatic encephalopathy seemed to worsen; and bradycardia developed in 1 patient. In another such programme, adverse effects occurred in about 2% of 5435 patients given cloral hydrate.2 Three reactions were described as lifethreatening.
1. Shapiro S, et al. Clinical effects of hypnotics II: an epidemiologic study. JAMA 1969; 209: 2016–20
2. Miller RR, Greenblatt DJ. Clinical effects of chloral hydrate in hospitalized medical patients. J Clin Pharmacol 1979; 19: 669–74.

Carcinogenicity.

Cloral hydrate has been widely used as a sedative, especially in children. Concern over warnings that cloral hydrate was carcinogenic in rodents1 has prompted some experts, including the American Academy of Pediatrics, to review the relative risks of the medical use of this drug.2,3 The original warnings appear to have been based, in part, on the assumption that cloral hydrate was a reactive metabolite of trichloroethylene and was responsible for its carcinogenicity, but there is evidence to suggest that the carcinogenicity of trichloroethylene is due to a reactive intermediate epoxide metabolite. Studies in vitro indicate that cloral hydrate can damage chromosomes in some mammalian test systems but there have been no studies of the carcinogenicity of cloral hydrate in humans. Some long-term studies in mice have linked cloral hydrate with the development of hepatic adenomas or carcinomas. However, it was noted that cloral hydrate was not the only sedative that had been shown to be a carcinogen in experimental animals. The American Academy of Pediatrics considered cloral hydrate to be an effective sedative with a low incidence of acute toxicity when given short-term as recommended and, although the information on carcinogenicity was of concern, it was not sufficient to justify the risk associated with the use of less familiar sedatives. There was no evidence in infants or children showing that any of the available alternatives were safer or more effective. However, the use of repetitive dosing with cloral hydrate to maintain prolonged sedation in neonates and other children was of concern because of the potential for accumulation of drug metabolites and resultant toxicity. A recent cohort study4 found no persuasive evidence to support a relationship between the use of cloral hydrate and the development of cancer. However, the statistical power was low for weak associations, particularly for some individual cancer sites.
1. Smith MT. Chloral hydrate warning. Science 1990; 250: 359
2. Steinberg AD. Should chloral hydrate be banned? Pediatrics 1993; 92: 442–6
3. American Academy of Pediatrics Committee on Drugs and Committee on Environmental Health. Use of chloral hydrate for sedation in children. Pediatrics 1993; 92: 471–3
4. Haselkorn T, et al. Short-term chloral hydrate administration and cancer in humans. Drug Safety 2006; 29: 67–77.

Effects on the CNS.

A 2-year-old child1 had the first of 2 seizures 60 minutes after receiving cloral hydrate 70 mg/kg for sedation.
1. Muñoz M, et al. Seizures caused by chloral hydrate sedative doses. J Pediatr 1997; 131: 787–8.

Hyperbilirubinaemia.

Small retrospective studies1 have suggested that prolonged use of cloral hydrate in neonates may be associated with the development of hyperbilirubinaemia. This may possibly be related to the prolonged half-life of the metabolite trichloroethanol in neonates.
1. Lambert GH, et al. Direct hyperbilirubinemia associated with chloral hydrate administration in the newborn. Pediatrics 1990; 86: 277–81.

Overdosage.

The general management of poisoning with cloral hydrate resembles that for barbiturates. Activated charcoal may be given orally to adults and children within 1 hour of ingestion of more than 30 mg/kg, provided that the airway can be protected; the value of gastric decontamination for overdose is uncertain. Of 76 cases of cloral hydrate poisoning reported to the UK National Poisons Information Service (NPIS), 47 were severe.1 Of 39 adults, 12 had cardiac arrhythmias including 5 with cardiac arrest. Antiarrhythmic drugs were recommended unless obviously contra-indicated. Haemoperfusion through charcoal or haemodialysis was recommended for patients in prolonged coma. Cardiac arrhythmias and CNS depression were also major features of 12 cases of cloral hydrate overdosage reported from Australia.2 Lidocaine was not always successful in controlling arrhythmias, but propranolol was successful in all 7 patients in whom it was used. It was noted that resistant arrhythmias, particularly ventricular fibrillation, ventricular tachycardia, and supraventricular tachycardia, were the usual cause of death in patients who had taken an overdosage of cloral hydrate. Although there had been no controlled studies of antiarrhythmic therapy in overdosage with cloral hydrate, the successful use of beta blockers appeared to be a recurring feature in reports in the literature. Indeed, the UK NPIS notes that tachyarrhythmias usually respond readily to an intravenous beta blocker such as esmolol or propranolol. Giving flumazenil produced an increased level of consciousness, pupillary dilatation, and return of respiratory rate and blood pressure towards normal in a patient who had taken an overdosage of cloral hydrate.3
1. Wiseman HM, Hampel G. Cardiac arrhythmias due to chloral hydrate poisoning. BMJ 1978; 2: 960
2. Graham SR, et al. Overdose with chloral hydrate: a pharmacological and therapeutic review. Med J Aust 1988; 149: 686–8
3. Donovan KL, Fisher DJ. Reversal of chloral hydrate overdose with flumazenil. BMJ 1989; 298: 1253.

💊 Precautions

Cloral hydrate should not be used in patients with marked hepatic or renal impairment or severe cardiac disease, and oral dosage is best avoided in the presence of gastritis. As with all sedatives, it should be used with caution in those with respiratory insufficiency. Cloral hydrate can cause drowsiness that may persist the next day; affected patients should not drive or operate machinery. Prolonged use and abrupt withdrawal of cloral hydrate should be avoided to prevent precipitation of withdrawal symptoms. Repeated doses in infants and children may lead to accumulation of metabolites and thereby increase the risk of adverse effects. Use is best avoided during pregnancy. Cloral hydrate may interfere with some tests for urinary glucose or 17-hydroxycorticosteroids.

Breast feeding.

The American Academy of Pediatrics1 states that, although usually compatible with breast feeding, use of cloral hydrate by breast-feeding mothers has been reported to cause sleepiness in the infant.
1. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. Correction. ibid.; 1029. Also available at: http://aappolicy.aappublications.org/cgi/content/full/ pediatrics%3b108/3/776 (accessed 28/04/04)

Neonates.

The half-life of trichloroethanol, an active metabolite of cloral hydrate, is prolonged in neonates;1 values of up to 66 hours have been reported in some studies. Short-term sedation in the neonate with single oral doses of 25 to 50 mg/kg of cloral hydrate is considered1 to be probably relatively safe, but repeated dosage carries the risk of accumulation of metabolites which may result in serious toxicity. Toxic reactions may occur even after the drug has been stopped since the metabolites may accumulate for several days.
1. Jacqz-Aigrain E, Burtin P. Clinical pharmacokinetics of sedatives in neonates. Clin Pharmacokinet 1996; 31: 423–43.

Obstructive sleep apnoea.

Children with obstructive sleep apnoea could be at risk from life-threatening respiratory obstruction if cloral hydrate is used for sedation. Details of 2 such children who suffered respiratory failure after sedation with cloral hydrate for lung function studies have been reported.1
1. Biban P, et al. Adverse effect of chloral hydrate in two young children with obstructive sleep apnea. Pediatrics 1993; 92: 461–3.

Porphyria.

UK licensed product information recommends that cloral hydrate should not be used in patients with porphyria, although some1 consider it safe; caution would seem appropriate.
1. Welsh Medicines Information Centre. Drugs that are considered to be safe for use in acute porphyrias. Available at: http:// www.wmic.wales.nhs.uk/pdfs/porphyria/PorphyriaSafeList.pdf (accessed 24/06/08)

💊 Interactions

The sedative effects of cloral hydrate are enhanced by other CNS depressants such as alcohol (the ‘Mickey Finn’ of detective fiction), barbiturates, and other sedatives. Cloral hydrate may alter the effects of coumarin anticoagulants. A hypermetabolic state, apparently due to displacement of thyroid hormones from their binding proteins, has been reported in patients given an intravenous dose of furosemide subsequent to cloral hydrate.

💊 Pharmacokinetics

Cloral hydrate is rapidly absorbed from the gastrointestinal tract and starts to act within 30 minutes of oral doses. It is widely distributed throughout the body. It is rapidly metabolised to trichloroethanol and trichloroacetic acid in the erythrocytes, liver, and other tissues. It is excreted partly in the urine as trichloroethanol and its glucuronide (urochloralic acid) and as trichloroacetic acid. Some is also excreted in the bile. Trichloroethanol is the active metabolite, and passes into the CSF, into breast milk, and across the placenta. The half-life of trichloroethanol in plasma is reported to range from about 7 to 11 hours but is considerably prolonged in the neonate. Trichloroacetic acid has a plasma half-life of several days.

💊 Uses and Administration

Cloral hydrate is a hypnotic and sedative with properties similar to those of the barbiturates. It is used in the short-term management of insomnia and has been used for sedation and as a sedative for premedication; its use as a hypnotic, particularly in children, is now limited. It has been widely used for sedation of children before diagnostic, dental, or medical procedures (but see under Carcinogenicity above). Externally, cloral hydrate has a rubefacient action and has been used as a counter-irritant. Cloral hydrate is given by mouth as an oral liquid or as gelatin capsules with cloral hydrate dissolved in a suitable vehicle. It has also been dissolved in a bland fixed oil and given by enema or as suppositories. It should not be given as tablets because of the risk of damage to the mucous membrane of the alimentary tract. The usual oral hypnotic dose in adults is 0.5 to 2 g given as a single dose at night; as a sedative 250 mg can be given three times daily to a maximum daily dose of 2 g. Oral dosage forms should be taken well diluted or with plenty of water or milk. The BNFC suggests that children aged 1 month to 12 years be given 30 to 50 mg/kg to a maximum single dose of 1 g by mouth as a hypnotic (but see above); those aged 12 to 18 years may be given 0.5 to 1 g. Although not licensed in the UK for sedation of children before a painless procedure, the BNFC suggests the following oral doses, given 45 to 60 minutes beforehand: 1 month to 12 years, 30 to 50 mg/kg (maximum of 1 g), although up to 100 mg/kg (maximum of 2 g) may be used with respiratory monitoring; 12 to 18 years, 1 to 2 g. The BNFC states that the doses above may be given rectally if the oral route is unavailable. In the USA, a suggested oral or rectal sedative dose for children is 8.3 mg/kg three times daily to a maximum daily dose of 1.5 g; a dose of 20 to 25 mg/kg has been given as a premedicant prior to EEG evaluation. A reduction in dosage may be appropriate in frail elderly patients or in those with hepatic impairment. Derivatives of cloral hydrate, such as cloral betaine (above), chloralose, and dichloralphenazone, which break down in the body to yield cloral hydrate, have been used similarly.
1. McCarver-May DG, et al. Comparison of chloral hydrate and midazolam for sedation of neonates for neuroimaging studies. J Pediatr 1996; 128: 573–6
2. Napoli KL, et al. Safety and efficacy of chloral hydrate sedation in children undergoing echocardiography. J Pediatr 1996; 129: 287–91.

💊 Preparations

USP 31: Chloral Hydrate Capsules; Chloral Hydrate Syrup.

Proprietary Preparations

Ger.: Chloraldurat; Switz.: Chloraldurat; Medianox; Nervifene; UK: Welldorm; USA: Aquachloral; Somnote. Multi-ingredient: Belg.: Dentophar; Sedemol; Sulfa-Sedemol; Synthol; Fr.: Bain de Bouche Lipha; Rus.: Efcamon (Эфкамон); Spain: Dentol Topico; Turk.: Dilan.
Published December 12, 2018.